Centralized vs. Onsite Monitoring

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Centralized vs. Onsite MonitoringApplying FDA’s Risk-Based

Approach

Sandra Maddock, RN, BSN, CCRAPresident, IMARC Research, Inc.

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Agenda

Overview of Monitoring

Monitoring Regulations/Standards

Current status

FDA’s DRAFT Guidance on Risk-based Monitoring

Application

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Overview of MonitoringDefinition

Qualifications

Purpose of monitoring

Day in the Life

Who monitors?

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• FDA Regulations• ICH Guidelines• ISO 14155:2011 (E)

Definition

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Definition

• FDA: 21 CFR 812.3 (j) – “When used as a noun, means an individual designated by a sponsor or contract research organization to oversee the progress of an investigation.”“When used as a verb, means to oversee an investigation.”

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Definition

• ICH GCP: 1.39 – “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs) GCP, and the applicable regulatory requirement(s).”

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Definition

• ISO 14155 3.29 –“act of overseeing the progress of a clinical investigation and to ensure that it is conducted, recorded, and reported in accordance with the CIP, written procedures, this International Standard, and the applicable regulatory requirements.”

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Qualifications

• Qualified by training and experience• Have scientific and/or clinical knowledge needed for

specific trial• Should be familiar with investigational products,

protocol, informed consent, pertinent aspects of the trial, GCP, and regulatory requirements

• Qualifications should be documented

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Purpose

• Verify:– Rights and well-being of human subjects are protected– Reported trial data are accurate, complete, and

verifiable– The conduct of the trial is in compliance with protocol,

GCP and applicable regulatory requirements

ICH 5.18.1ISO 8.2.4

FDA’s draft guidance

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Day in the Life• Review regulatory

documents• Verify source data• Issue queries on the CRFs

(EDC or paper)• Address and resolve

queries with site staff• Perform device

accountability

• Address action items from previous visits

• Meet with PI, Co-I, or CRC to discuss findings

• Train staff on protocol requirements

• Assess continued acceptability of site to perform protocol requirements… and so much more!

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Who Monitors?• Physicians• Nurses• Biomedical Engineers• Public Health workers• Biology majors• Pharmacists• And more….


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Regulations: FDA

Standards: FDA Guidelines

Standards: ICH Guidelines

Standards: ISO 14155:2011 (E)

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• Sponsor requirements noted in various places throughout 21 CFR 812 & 312:– 21 CFR 812.25: Investigational plan shall include the monitoring

procedures and the name/address of the monitor(s)– 21 CFR 812.40: “… ensure proper monitoring of the investigation,

ensuring that IRB review and approval are obtained, …..”– 21 CFR 312.50: “…ensuring proper monitoring of the investigation(s),

ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols “

Regulations: FDA

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• Sponsor requirements noted in various places: – 21 CFR 312.50- General Responsibilities of Sponsors– 21 CFR 812.46 (a) Sponsors shall secure compliance with

• Investigational Plan• Regulations• Conditions imposed by IRB or FDA

– If non-compliance continues• Discontinue shipment of investigational product• Terminate participation in investigation

Regulations: FDA

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• Guideline for Monitoring Clinical Investigations, January 1988– Vague in its requirements– Effective monitoring requires personal contact between

the monitor and the investigator throughout the trial

Standards: FDA Guidelines

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• April 1996• Pharmaceutical-focused• Began laying the groundwork for a risk-based

approach: extent and nature of monitoring should depend on “the objective, purpose, design, complexity, blinding, size, and endpoints of the trial…”

Standards: ICH Guidelines

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• 2011• Device focused• Monitoring plan shall take into account “..objective,

design, complexity, size, critical data points and endpoints…”

• However, it also indicates that monitors shall conduct “routine on-site monitoring visits…”

Standards: ISO Guidelines

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Current Status

General Industry Practice

Our Report Card

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Current Practice

General Industry Practice“Many sponsors have understood these guidances as contributing to the notion that FDA expects sponsors to conduct frequent on-site monitoring and 100% verification for all trials, regardless of their design and complexity.”

-FDA’s DRAFT Risk-Based Monitoring Guidance

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Current Practice

• Monitoring of 100% source data• Monitoring conducted at pre-determined time

intervals, for example…– Every 4-6 weeks– Every 5th patient– At least once a quarter

General Industry Practice

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Current Practice

• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2007: • 46% of sponsors inspected had voluntary or official action

indicated• Most common citings:

– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability

Our Report Card

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Current Practice




Our Report Card

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Current Practice




Our Report Card

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Current Practice




Our Report Card

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Current Practice




Our Report Card

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Current Practice

–Inadequate monitoring–Failure to bring investigators into compliance–Inadequate accountability

Our Report Card

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FDA’s Guidance on Risk-Based Monitoring

DRAFT

Introduction

Rationale

General Recommendations

Monitoring Plan

Documentation

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Introduction

• Assist sponsors in developing monitoring strategies• Enhance human subject protection• Enhance the quality of clinical trial data

Variety of approaches

DRAFT

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• Provide increased ability to protect patients– Not caught up in the minute details, but rather focused

on key data points• Improve overall study quality• Monitor more effectively

DRAFT

Rationale

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• Tasks that historically could only be done on-site, may now be done remotely due to technology– EDC systems– Webcasts– Email– Online Training Modules

DRAFT

Rationale

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• No single approach can work for every clinical study

• Modify based on risks of the trial• Include mix of centralized and on-site• Document intended approach in a monitoring plan

DRAFT


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• On-site monitoring activities:– Source data verification– Verification that study documentation exists– Assessment of site’s familiarity and compliance with

protocol– Investigational product accountability– Get a general sense of how things are going at a site

DRAFT


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• Centralized monitoring activities:– Standard checks (ranges, blanks, unusual data,

outliers)– Identify sites with more errors, dropouts, protocol

violations– Data trends– Verify source data remotely (when applicable)

DRAFT


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• Centralized monitoring can assess:– Analyze site characteristics (high screen failure rates,

eligibility violations, delays in submitting data)– Collect – Review – and archive regulatory documents

DRAFT


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• Use of both types of monitoring is encouraged• Greater emphasis of on-site monitoring may be

required earlier in the study

DRAFT


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• Higher frequency monitoring may be needed to assess:– Critical study endpoints– Safety assessments– Documentation surrounding serious adverse

events/unanticipated adverse device effects– Eligibility criteria

DRAFT


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• Higher frequency monitoring may be needed to assess:– That study blind is maintained– Product accountability

DRAFT


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• Monitoring plan considerations– Complexity of the study design– Types of study endpoints– Clinical complexity of the study population– Geography

DRAFT


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• Monitoring plan considerations– Experience of the clinical investigation site– EDC considerations– Relative safety of the investigational product– Stage of the study– Quantity of data

DRAFT


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• What should be included?– Description of monitoring methods to be employed– Criteria for determining timing, frequency, and intensity of

monitoring– Reference to any tools that will be used (i.e., checklists)– Identification of events that may trigger changes– Identification of deviations or failures that would be critical to

study integrity

DRAFT

Monitoring Plan

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• What should be included?– When writing your monitoring plan, define the activities you

will be doing centrally and those that you will be doing on-site• i.e., centralized monitoring will consist of remote review of regulatory

documentation including CVs, licenses, IRB correspondence, etc.• i.e., onsite monitoring will consist of review of informed consent

documents, source data, product accountability, etc.

DRAFT

Monitoring Plan

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• Communication of monitoring results is critical to effective implementation

DRAFT

Monitoring Plan

Management

On-site Monitor

Data Management

Internal Study Team

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• Managing Non-compliances

DRAFT

What action is indicated?

Data Mgmt

Monitor

Internal Study Team

Monitoring Plan

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• Special Training Requirements?– For on-site monitors?– For centralized “monitors”?

• Planned Quality Checks?• Reference to SOPs

DRAFT

Monitoring Plan

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• Amendments to the monitoring plan– What “triggers” would require review and revision– Consider writing the monitoring plan broadly enough to

include built-in flexibility

DRAFT

Monitoring Plan

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• For on-site traditional monitoring reports• For centralized use what works within your

system– Cover sheets, cumulative electronic log of deficiencies,

centralized “work space” to list study-related issues, etc.

• Incorporate into quality system; note in monitoring plan

DRAFT

Documentation

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Application

Case Study• Significant risk implantable device study• Device is relatively complicated to deploy• Study conducted at 20 US-based sites• Both experienced and research-naïve sites

involved in the trial• EDC being utilized

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Application

• Sites are asked to email PDFs of regulatory documents

• Screening logs gets faxed every week• Once every 3 months, the sites are asked to fax

product accountability logs

Case Study

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Application

Administrative:• Write monitoring plan to include strategy for

centralized and on-site monitoring• Train staff on expectations, including relevant

procedures, checklists, etc.• Determine mechanism for communicating

Case Study

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Application

On-site Monitors:• Conduct site initiation visits• Monitor each site’s first 3 patients• Monitor research-naïve sites on regular basis until

competency determined (define threshold)• Monitor other sites as needed based on central

monitoring activity

Case Study

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Application

On-site Monitors:• Conduct periodic product accountability• Assess site’s continued adequacy for conducting study• Conduct focused assessment of regulatory documents• Review adverse events• Secure compliance (regardless of origin of finding)• Report to study team

Case Study

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Application

Centralized “monitors”:• Review EDC for:– Standard range checks– Consistency of data– Completeness of data– Unusual distribution (i.e., too little variance)– Adverse event assessment– Eligibility criteria

Case Study

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Application

Centralized “monitors”:• Review regulatory documents – Think beyond just logging them in and filing them. Read and

understand them within each site’s context.• CV that hasn’t been updated in 10 years• IRB approval letter that lists the wrong study or approves a

consent form that you do not have on file

Case Study

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Application

Centralized “monitors”:• Assess overall site performance– Is data timely?– Are they responsive to query requests?– Are they available?– Can they readily retrieve needed documentation?

Case Study

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Application

Communicate• Issues get discussed in a team meeting• Deficiencies noted in central electronic “workspace” • Monitoring effort re-evaluated regularly• Project manager determines that increased or decreased

frequency for a particular site is appropriate

Case Study

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Application

Result?• Could be more efficient use of on-site monitors’ time– Time spent on critical areas as opposed to administrative areas

• Cost savings due to decreased number of trips and/or decreased amount of time needed at sites for each visit

• Sites may appreciate having less on-site monitoring

Case Study

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4 Main Points• We’re all “monitors” in some capacity• Determining the nature and frequency of monitoring

requires a risk-based assessment• Documenting all monitoring activity and

communicating findings is essential to successful implementation

• Utilizing central monitors to help direct on-site monitoring efforts can increase efficiency and decrease cost

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Thank You!

QUESTIONS?

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References

• FDA Guidance: Risk-Based Approach to Monitoring (2011). Retrieved from http://1.usa.gov/rjmVrh

• FDA Guidance: Monitoring of Clinical Investigations (1988).• Code of Federal Regulations: 21 CFR 812• Guidance for Industry, E6 Good Clinical Practice• International Standards ISO 14155:2011 (E)• FDA’s Annual BIMO Inspection Metrics (2007-2011). Retrieved from

http://1.usa.gov/HLS1Lt

http://1.usa.gov/rjmVrh

http://1.usa.gov/rjmVrh



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Centralized vs. Onsite Monitoring